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Yu Zhou Central Laboratory, Translational Medicine Research Center, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
Department of Obstetrics and Gynecology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China

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Chao Lian Central Laboratory, Translational Medicine Research Center, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China

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Yingfei Lu Central Laboratory, Translational Medicine Research Center, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China

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Tianming Wang Central Laboratory, Translational Medicine Research Center, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China

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Chengcheng Zhao Central Laboratory, Translational Medicine Research Center, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China

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Cuilan Zhang Department of Obstetrics and Gynecology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China

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Min Gong Department of Obstetrics and Gynecology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China

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Jianquan Chen Central Laboratory, Translational Medicine Research Center, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
Department of Obstetrics and Gynecology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China

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Rong Ju Department of Obstetrics and Gynecology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China

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Polycystic ovary syndrome (PCOS) is a condition resulting from the interaction between environmental factors and hereditary components, profoundly affecting offspring development. Although the etiology of this disease remains unclear, aberrant in utero androgen exposure is considered one of the pivotal pathogenic factors. Herein, we demonstrate the intergenerational inheritance of PCOS-like phenotypes in F2 female offspring through F1 males caused by maternal testosterone exposure in F0 mice. We found impaired serum hormone expression and reproductive system development in prenatal testosterone-treated F1 male and F2 female mice (PTF1 and PTF2). In addition, downregulated N6-methyladenosine (m6A) methyltransferase and binding proteins induced mRNA hypomethylation in the PTF1 testis, including frizzled-6 (Fzd6). In the PTF2 ovary, decreased FZD6 protein expression inhibited the mammalian target of rapamycin (mTOR) signaling pathway and activated Forkhead box O3 (FoxO3) phosphorylation, which led to impaired follicular development. These data indicate that epigenetic modification of the mTOR signaling pathway could be involved in the intergenerational inheritance of maternal testosterone exposure-induced impairments in the PTF2 ovary through male PTF1 mice.

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Xuan Zhou Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China

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Yanan Zhang Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China

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Youwen Yuan Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China

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Fei Teng Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China

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Jiayang Lin Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China

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Xueru Ye Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China

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Yaojin Pan Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China

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Huijie Zhang Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China

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Characteristic symptoms of hyperthyroidism include weight loss, heart palpitation, and sweating. Thyroid hormones (TH) can stimulate thermogenesis through central and peripheral mechanisms. Previous studies have shown an association between dysfunction of cardiotrophin-like cytokine factor 1 (CLCF1) and cold-induced sweating syndrome, with recent research also indicating a link between CLCF1 and brown adipose tissue thermogenesis. However, it remains unclear whether CLCF1 and TH have synergistic or antagonistic effects on thermogenesis. This study aims to investigate the influence of thyroid hormone on circulating CLCF1 levels in humans and explore the potential possibilities of thyroid hormone in regulating energy metabolism by modulating Clcf1 in mice. By recruiting hyperthyroid patients and healthy subjects, we observed significantly lower serum CLCF1 levels in hyperthyroid patients compared to healthy subjects, with serum CLCF1 levels independently associated with hyperthyroidism after adjusting for potential confounders. Tissue analysis from mice treated with T3 revealed a decrease in CLCF1 expression in BAT and iWAT of C57BL/6 mice. These findings suggest that TH may play a role in regulating CLCF1 expression in adipose tissue.

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Kaitlyn A Colglazier Lilly Diabetes Center of Excellence, Indiana Biosciences Research Institute, Indianapolis, Indiana, USA

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Noyonika Mukherjee Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA

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Christopher J Contreras Division of Endocrinology, Department of Medicine, Roudebush VA Medical Center and Indiana University School of Medicine, Indianapolis, Indiana, USA

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Andrew T Templin Lilly Diabetes Center of Excellence, Indiana Biosciences Research Institute, Indianapolis, Indiana, USA
Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
Division of Endocrinology, Department of Medicine, Roudebush VA Medical Center and Indiana University School of Medicine, Indianapolis, Indiana, USA
Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA

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β-Cell death contributes to β-cell loss and insulin insufficiency in type 1 diabetes (T1D), and this β-cell demise has been attributed to apoptosis and necrosis. Apoptosis has been viewed as the lone form of programmed β-cell death, and evidence indicates that β-cells also undergo necrosis, regarded as an unregulated or accidental form of cell demise. More recently, studies in non-islet cell types have identified and characterized novel forms of cell death that are biochemically and morphologically distinct from apoptosis and necrosis. Several of these mechanisms of cell death have been categorized as forms of regulated necrosis and linked to inflammation and disease pathogenesis. In this review, we revisit discoveries of β-cell death in humans with diabetes and describe studies characterizing β-cell apoptosis and necrosis. We explore literature on mechanisms of regulated necrosis including necroptosis, ferroptosis and pyroptosis, review emerging literature on the significance of these mechanisms in β-cells, and discuss experimental approaches to differentiate between various mechanisms of β-cell death. Our review of the literature leads us to conclude that more detailed experimental characterization of the mechanisms of β-cell death is warranted, along with studies to better understand the impact of various forms of β-cell demise on islet inflammation and β-cell autoimmunity in pathophysiologically relevant models. Such studies will provide insight into the mechanisms of β-cell loss in T1D and may shed light on new therapeutic approaches to protect β-cells in this disease.

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Renata Risi Department of Experimental Medicine, Sapienza University of Rome, Sapienza University of Rome, Rome, Italy
University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK

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Antonio Vidal-Puig University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK
Cambridge University Nanjing Centre of Technology and Innovation, Nanjing, P. R. China
Centro de Investigacion Principe Felipe, Valencia, Spain

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Guillaume Bidault University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK

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Obesity and diabetes represent two increasing and invalidating public health issues that often coexist. It is acknowledged that fat mass excess predisposes to insulin resistance and type 2 diabetes mellitus (T2D), with the increasing incidence of the two diseases significantly associated. Moreover, emerging evidence suggests that obesity might also accelerate the appearance of type 1 diabetes (T1D), which is now a relatively frequent comorbidity in patients with obesity. It is a common clinical finding that not all patients with obesity will develop diabetes at the same level of adiposity, with gender, genetic, and ethnic factors playing an important role in defining the timing of diabetes appearance. The adipose tissue (AT) expandability hypothesis explains this paradigm, indicating that the individual capacity to appropriately store energy surplus in the form of fat within the AT determines and prevents the toxic deposition of lipids in other organs, such as the pancreas. Thus, we posit that when the maximal storing capacity of AT is exceeded, individuals will develop T2D. In this review, we provide insight into mechanisms by which the AT controls pancreas lipid content and homeostasis in case of obesity to offer an adipocentric perspective of pancreatic lipotoxicity in the pathogenesis of diabetes. Moreover, we suggest that improving AT function is a valid therapeutic approach to fighting obesity-associated complications including diabetes.

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Xiong Weng Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, UK

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Hao Jiang Gene Expression and Regulation, School of Life Sciences, University of Dundee, Dundee, Scotland, UK

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David J Walker Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, UK

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Houjiang Zhou MRC Protein Phosphorylation Unit, School of Life Sciences, Dundee, Scotland, UK

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De Lin Drug Discovery Unit, School of Life Sciences, University of Dundee, Dundee, Scotland, UK

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Jing Wang Science for Life Laboratory, Department of Biomedical and Clinical Sciences (BKV), Linköping University, Linköping, Sweden

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Li Kang Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, UK

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CD44, a cell surface adhesion receptor and stem cell biomarker, is recently implicated in chronic metabolic diseases. Ablation of CD44 ameliorates adipose tissue inflammation and insulin resistance in obesity. Here, we investigated cell type-specific CD44 expression in human and mouse adipose tissue and further studied how CD44 in preadipocytes regulates adipocyte function. Using Crispr Cas9-mdediated gene deletion and lentivirus-mediated gene re-expression, we discovered that deletion of CD44 promotes adipocyte differentiation and adipogenesis, whereas re-expression of CD44 abolishes this effect and decreases insulin responsiveness and adiponectin secretion in 3T3-L1 cells. Mechanistically, CD44 does so via suppressing Pparg expression. Using quantitative proteomics analysis, we further discovered that cell cycle-regulated pathways were mostly decreased by deletion of CD44. Indeed, re-expression of CD44 moderately restored expression of proteins involved in all phases of the cell cycle. These data were further supported by increased preadipocyte proliferation rates in CD44-deficient cells and re-expression of CD44 diminished this effect. Our data suggest that CD44 plays a crucial role in regulating adipogenesis and adipocyte function possibly through regulating PPARγ and cell cycle-related pathways. This study provides evidence for the first time that CD44 expressed in preadipocytes plays key roles in regulating adipocyte function outside immune cells where CD44 is primarily expressed. Therefore, targeting CD44 in (pre)adipocytes may provide therapeutic potential to treat obesity-associated metabolic complications.

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Katherine N Balantekin Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York, USA
Center for Ingestive Behavior Research, University at Buffalo, Buffalo, New York, USA

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Martin J Kretz Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York, USA

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Elizabeth G Mietlicki-Baase Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York, USA
Center for Ingestive Behavior Research, University at Buffalo, Buffalo, New York, USA

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Binge eating is a central component of two clinical eating disorders: binge eating disorder and bulimia nervosa. However, the large treatment gap highlights the need to identify other strategies to decrease binge eating. Novel pharmacotherapies may be one such approach. Glucagon-like peptide-1 (GLP-1) is an intestinal and brain-derived neuroendocrine signal with a critical role in promoting glycemic control through its incretin effect. Additionally, the energy balance effects of GLP-1 are well-established; activation of the GLP-1 receptor (GLP-1R) reduces food intake and body weight. Aligned with these beneficial metabolic effects, there are GLP-1R agonists that are currently used for the treatment of diabetes and obesity. A growing body of literature suggests that GLP-1 may also play an important role in binge eating. Dysregulation of the endogenous GLP-1 system is associated with binge eating in non-human animal models, and GLP-1R agonists may be a promising approach to suppress the overconsumption that occurs during binge eating. Here, we briefly discuss the role of GLP-1 in normal energy intake and reward and then review the emerging evidence suggesting that disruptions to GLP-1 signaling are associated with binge eating. We also consider the potential utility of GLP-1-based pharmacotherapies for reducing binge eating behavior.

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Graham W Aberdeen Departments of Obstetrics, Gynecology, Reproductive Sciences and Physiology, University of Maryland School of Medicine, Baltimore, Maryland, USA

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Jeffery S Babischkin Departments of Obstetrics, Gynecology, Reproductive Sciences and Physiology, University of Maryland School of Medicine, Baltimore, Maryland, USA

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Gerald J Pepe Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia, USA

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Eugene D Albrecht Departments of Obstetrics, Gynecology, Reproductive Sciences and Physiology, University of Maryland School of Medicine, Baltimore, Maryland, USA

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We recently showed that the ratio of capillaries to myofibers in skeletal muscle, which accounts for 80% of insulin-directed glucose uptake and metabolism, was reduced in baboon fetuses in which estrogen was suppressed by maternal letrozole administration. Since vascular endothelial growth factor (VEGF) promotes angiogenesis, the present study determined the impact of estrogen deprivation on fetal skeletal muscle VEGF expression, capillary development, and long-term vascular and metabolic function in 4- to 8-year-old adult offspring. Maternal baboons were untreated or treated with letrozole or letrozole plus estradiol on days 100–164 of gestation (term = 184 days). Skeletal muscle VEGF protein expression was suppressed by 45% (P < 0.05) and correlated (P = 0.01) with a 47% reduction (P < 0.05) in the number of capillaries per myofiber area in fetuses of baboons in which serum estradiol levels were suppressed 95% (P < 0.01) by letrozole administration. The reduction in fetal skeletal muscle microvascularization was associated with a 52% decline (P = 0.02) in acetylcholine-induced brachial artery dilation and a 23% increase (P = 0.01) in mean arterial blood pressure in adult progeny of letrozole-treated baboons, which was restored to normal by letrozole plus estradiol. The present study indicates that estrogen upregulates skeletal muscle VEGF expression and systemic microvessel development within the fetus as an essential programming event critical for ontogenesis of systemic vascular function and insulin sensitivity/glucose homeostasis after birth in primate offspring.

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Se-Min Kim The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Farhath Sultana The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Steven Sims The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Judit Gimenez-Roig The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Victoria Laurencin The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Anusha Pallapati The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Satish Rojekar The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Tal Frolinger The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Weibin Zhou The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Anisa Gumerova The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Anne Macdonald The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Vitaly Ryu The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Daria Lizneva The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Funda Korkmaz The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Tony Yuen The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Mone Zaidi The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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The pituitary gland orchestrates multiple endocrine organs by secreting tropic hormones, and therefore plays a significant role in a myriad of physiological processes, including skeletal modeling and remodeling, fat and glucose metabolism, and cognition. Expression of receptors for each pituitary hormone and the hormone itself in the skeleton, fat, immune cells, and the brain suggest that their role is much broader than the traditionally attributed functions. FSH, believed solely to regulate gonadal function is also involved in fat and bone metabolism, as well as in cognition. Our emerging understanding of nonreproductive functions of FSH, thus, opens potential therapeutic opportunities to address detrimental health consequences during and after menopause, namely, osteoporosis, obesity, and dementia. In this review, we outline current understanding of the cross-talk between the pituitary, bone, adipose tissue, and brain through FSH. Preclinical evidence from genetic and pharmacologic interventions in rodent models, and human data from population-based observations, genetic studies, and a small number of interventional studies provide compelling evidence for independent functions of FSH in bone loss, fat gain, and congnitive impairment.

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Jane Stremming Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

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Eileen I Chang Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

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Alicia White Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

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Paul J Rozance Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

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Laura D Brown Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

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Insulin-like growth factor 1 (IGF-1) is a critical fetal anabolic hormone. IGF-1 infusion to the normally growing sheep fetus increases the weight of some organs but does not consistently increase body weight. However, IGF-1 infusion profoundly decreases fetal plasma insulin concentrations, which may limit fetal growth potential. In this study, normally growing late-gestation fetal sheep received an intravenous infusion of either: IGF-1 (IGF), IGF-1 with insulin and dextrose to maintain fetal euinsulinemia and euglycemia (IGF+INS), or vehicle control (CON) for 1 week. The fetus underwent a metabolic study immediately prior to infusion start and after 1 week of the infusion to measure uterine and umbilical uptake rates of nutrients and oxygen. IGF+INS fetuses were 23% heavier than CON (P = 0.0081) and had heavier heart, liver, and adrenal glands than IGF and CON (P < 0.01). By design, final fetal insulin concentrations in IGF were 62% and 65% lower than IGF+INS and CON, respectively. Final glucose concentrations were similar in all groups. IGF+INS had lower final oxygen content than IGF and CON (P < 0.0001) and lower final amino acid concentrations than CON (P = 0.0002). Final umbilical oxygen uptake was higher in IGF+INS compared to IGF and CON (P < 0.05). Final umbilical uptake of several essential amino acids was higher in IGF+INS compared to CON (P < 0.05). In summary, maintaining euinsulinemia and euglycemia during fetal IGF-1 infusion is necessary to maximally support body growth. We speculate that IGF-1 and insulin stimulate placental nutrient transport to support fetal growth.

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Galit Levi Dunietz Department of Neurology, Division of Sleep Medicine, University of Michigan, Ann Arbor, Michigan, USA

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Lucas J Tittle Department of Psychology, University of Michigan, Ann Arbor, Michigan, USA

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Sunni L Mumford Department of Biostatistics, Epidemiology and Informatics and Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

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Louise M O’Brien Department of Neurology, Division of Sleep Medicine, University of Michigan, Ann Arbor, Michigan, USA
Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, USA

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Ana Baylin Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA

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Enrique F Schisterman Department of Biostatistics, Epidemiology and Informatics and Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

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Ronald D Chervin Department of Neurology, Division of Sleep Medicine, University of Michigan, Ann Arbor, Michigan, USA

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Larry J Young Center for Translational Social Neuroscience, Emory National Primate Research Center, Emory University, Atlanta, Georgia, USA
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA

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Menopause marks the cessation of fertility and the transition to post-reproductive years. Nearly 1 million US women experience menopause annually, but despite the significant impact it has on their physical and mental health, menopause has been insufficiently studied. Oxytocin is a neurohormone that regulates emotionality, social behaviors, and fundamental physiological systems. Localization of oxytocin receptors in the brain, reproductive tissues, bone, and heart support their role in mental health and potentially sleep, along with reproductive and cardiovascular functions. While experimental data linking oxytocin to behavior and physiology in animals are largely consistent, human data are correlative and inconclusive. As women transition into menopause, oxytocin levels decrease while their susceptibility to mood disorders, poor sleep, osteoporosis, and cardiovascular diseases increases. These concurrent changes highlight oxytocin as a potential influence on the health and mood of women along their reproductive life span. Here, we summarize experimental rodent and non-human primate studies that link oxytocin to reproductive aging and metabolic health and highlight the inconclusive findings in studies of women. Most human studies relied on a single oxytocin assessment in plasma or on intranasal oxytocin administration. The pulsatile release and short half-life of plasma oxytocin limit the validity of these methods. We discuss the need for oxytocin assessments in stable bio-samples, such as urine, and to use valid assays for assessment of associations between changing oxytocin levels and well-being across the reproductive life span. This work has the potential to guide therapeutic strategies that will one day alleviate adverse health outcomes for many women.

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